Current advances in the treatment of multiple myeloma (MM) have resulted in a high rate of remissions; however, all patients eventually relapse and succumb to the disease. Cells in the bone marrow microenvironment are intimately involved in the disease process as regulators of myeloma growth and tumor manifestations. MM cells enhance bone resorption by triggering a coordinated increase in the receptor activator of nuclear factor-: B ligand (RANKL) and a decrease in osteoprotegerin (OPG) in the bone marrow. Further, osteoclasts enhance angiogenesis in concert with MM cells largely through the cooperative actions of osteopontin from osteoclasts and vascular endothelial growth factor (VEGF) from MM cells. The angiogenic effect further facilitates the vicious cycle between bone destruction and MM cell expansion. Thus, development of new, targeted therapies to abrogate key events of osteolytic bone destruction, MM cell growth and associated pathology of tumor angiogenesis, will lead to better management of the disease and increase patient survival. The overall goal of this proposal is to develop a new paradigm of myeloma therapy, whereby control of bone disease, tumor angiogenesis and tumor cells by targeted therapies to these events will help to control myeloma progression. We recently developed a novel method for bone enriched homing of genetically transduced MSC and demonstrated the potential of such MSC, modified to express OPG, in preventing osteolytic bone damage. Further, by using a recombinant adeno-associated virus vector (rAAV) encoding endostatin and angiostatin, we demonstrated significant delay in tumor growth and increase in long-term survival. In the proposed studies, we will determine the effects of these therapies in step-wise combination with chemotherapy in a mouse model of MM, which closely mimics the human disease pathology. The results of the proposed study will lead us to the next stage in which we will design treatment protocols aimed at improving myeloma-related bone disease and test treatment efficacy in preventing myeloma relapses and disease progression in human patients.